An orally active FSH agonist has been the futuristic goal of infertility treatments since the inception of injectable therapies. We are developing oral FSH agonists to improve the convenience of treatment for patients undergoing controlled ovarian hyperstimulation followed by in vitro fertilization, to provide a superior treatment option for mild ovarian stimulation followed by ovulation induction, and to develop the first prescription product for treatment of male factor infertility.
Reproductive endocrinologists, the experts in infertility treatments, have provided enthusiastic support for development of oral FSH agonists. Currently, women undergoing controlled ovarian hyperstimulation prior to in vitro fertilization receive 30-40 injections per cycle, and women undergoing milder ovarian stimulation prior to intrauterine insemination receive 10-14 injections. Women also undergo similar ovarian stimulation even if their male partner is the infertile patient because there is no approved therapy for men. Most women will require at least 2 cycles of ovarian stimulation in order to become pregnant and take home their baby.
Dr. Michael Alper (co-founder Boston IVF, Associate Clinical Professor at Harvard Medical School, has led several research studies sponsored by the National Institutes of Health (NIH). His focus of research has been to maintain the highest quality of treatment in IVF and in other areas of clinical and scientific research such as egg freezing and fertility diagnostics. Following an overview of the program, he commented, “an orally active FSH receptor agonist with similar activity as the injectable products will be a disruptive innovation for treatment of both female and male infertility.”
Professor Bruno Lunenfeld is best known for his pioneering work in human reproduction, especially for extraction, and purification of urinary gonadotropins. He was the first to introduce human Menopausal Gonadotropins (hMG) for clinical use (1953-1961) in anovulatory women and hypopituitary-hypogonadotropic men.
He was instrumental in the creation of an international standard for Gonadotropins, the classification of infertile patients and of the hyperstimulation syndrome. He has made significant contributions to the understanding of follicular recruitment, rescue, selection, growth and development, the ovulatory cycle and the mechanism of action of gonadotropins in ovaries and testis.
“In the 1960s we were pioneers, treating infertility in women with purified hormones isolated from the urine of postmenopausal nuns. Over the next few years we obtained highly purified hFSH through immuno –purification. A few decades later, a new set of scientists transformed this treatment with use of recombinant preparations that provided a more consistent dosing regimen. Over the last 50 years, those of us who founded this field always dreamed that someday an oral FSH preparation could be available. TocopheRx seems positioned to achieve this dream.”
FSH (blue; 33kD) and the inactive FSH receptor (magenta & gray; 75 kD), are both large proteins. TocopheRx has successfully developed innovative small molecules (gold) that directly activate the transmembrane domain (green). TocopheRx allosteric agonists (TOPs) enhance the response of the FSH receptor when a small amount of FSH is present, or act as a receptor agonist in the absence of endogenous FSH.
Jiang et al., 2014, J Biol. Chem 289 (20):14273-14282